5-Azacitidine + Decitabine for Myelodysplastic Syndrome

Overseen By Benjamin Tomlinson, MD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Benjamin Tomlinson

Must not be taking: Azacitidine, Decitabine, Guadecitibine

Disqualifiers: High risk MDS, Pregnancy, Uncontrolled illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for myelodysplastic syndrome (MDS), a condition where the bone marrow fails to produce healthy blood cells properly. It combines two existing drugs, 5-azacitidine (Vidaza) and decitabine (Dacogen), administered in low doses to halt abnormal cell growth without the usual harsh side effects. Suitable candidates for this trial include those with MDS who experience symptoms like anemia or require regular blood transfusions. As an Early Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the chance to contribute to groundbreaking medical advancements.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications, but it does mention that no other disease-directed therapy, except for hydroxyurea, is allowed 14 days before starting the study. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both 5-azacitidine (5AZA) and decitabine (DEC) have FDA approval for treating myelodysplastic syndromes (MDS), indicating they have been tested for safety in people with this condition. Studies have found that azacitidine can help MDS patients live longer, though it may cause side effects. Common side effects include decreased bone marrow activity, leading to fewer blood cells and infections.

Less information exists about the safety of using 5AZA and DEC together. However, both drugs are effective individually for MDS. This trial is in its early stages, primarily focusing on the safety of using these drugs in combination. As a result, there might be limited information on how well people tolerate both drugs at this stage. Still, the FDA's approval of each drug individually for MDS provides some reassurance about their safety in people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of 5-azacytidine and Decitabine for treating Myelodysplastic Syndrome because it introduces a new dosing schedule that might enhance effectiveness. Unlike standard treatments, which often involve separate cycles for each drug, this approach combines both in a weekly regimen. This novel schedule aims to maximize the benefits of both drugs, potentially offering improved outcomes by maintaining consistent therapeutic levels. Additionally, the dual action of these medications targets the DNA of cancer cells, disrupting their growth and survival more effectively than current options.

What evidence suggests that this trial's treatments could be effective for myelodysplastic syndrome?

Research has shown that the drugs 5-azacitidine (5AZA) and decitabine (DEC) effectively treat myelodysplastic syndrome (MDS). The FDA has approved both for MDS, a condition where the bone marrow doesn't produce enough healthy blood cells. One study highlighted that 5AZA can help patients with higher-risk MDS live longer. Another study suggested that using these drugs can lead to significant survival benefits. In this trial, participants will receive 5AZA and DEC in alternating low doses to overcome resistance that can occur when used alone. This approach may help manage MDS more effectively. ^{1 3 6 7 8}

Who Is on the Research Team?

Benjamin Tomlinson, MD

Principal Investigator

Cleveland Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals with myelodysplastic syndrome or related disorders who may benefit from HMA therapy. They must be in a condition to perform daily activities at least 60% of their capacity and have organs functioning well enough to handle the treatment. Participants need to understand and consent to the study, but can't join if they've had certain high-risk MDS, previous similar treatments, other ongoing conditions that could affect safety, are pregnant/breastfeeding, unwilling to use contraception or have unresolved severe side effects from past therapies.

Inclusion Criteria

My organs are functioning well.

I have MDS or MDS/myeloproliferative disorder and may respond to HMA therapy.

I am mostly independent and can care for myself.

Exclusion Criteria

Any severe side effects from my previous cancer treatments have improved.

You have any other medical condition that could make it unsafe for you to participate in the study or could make it difficult to accurately evaluate the study results.

Currently pregnant or breast-feeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive 5-azacytidine and decitabine in an alternating low dose schedule to induce response

8 weeks

Weekly visits for drug administration

Long-term Treatment

Participants continue treatment with 5-azacytidine and decitabine until disease progression or relapse

Minimum of 16 weeks

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years from end of treatment

What Are the Treatments Tested in This Trial?

Interventions

• 5-azacytidine
• Decitabine

Trial Overview The trial tests alternating low doses of two FDA-approved chemotherapy drugs, 5-azacytidine (5AZA) and decitabine (DEC), for treating bone marrow failure syndromes like myelodysplastic syndrome. The goal is to see if this approach can overcome resistance seen when these drugs are used alone by affecting DNA metabolism in abnormal cells.

How Is the Trial Designed?

Group I: 5AZA-alt-DEC Experimental Treatment 2 Interventions

Participants will be treated for a minimum of 24 weeks in the absence of clear evidence of progressive disease. Patients who have any response will be permitted to continue treatment until relapse or progression of disease that is not sensitive to protocol defined dose escalation. Treatments will include: 5-azacytidine (50mg/m\^2) Day 1 every week Decitabine (5mg/m\^2) Day 4 every week Weeks 1-8 will be an induction phase, and weeks 9+ will be a long-term treatment phase

5-azacytidine is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in European Union as Azacitidine for:

• Myelodysplastic syndromes
• Acute myeloid leukemia
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Azacitidine for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Benjamin Tomlinson

Lead Sponsor

Trials

4

Recruited

110+

Published Research Related to This Trial

In a study of 1406 patients receiving azacitidine, the most common severe adverse events were hematologic, with grade 3-4 anemia occurring in 43.4% of patients, which was higher than reported in clinical trials.

Despite the high frequency of adverse events, treatment discontinuation due to these events was low (5.1%), indicating that with proper management, azacitidine can be safely administered to most patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents-A Prospective Cohort Study of the AGMT Study-Group. Leisch, M., Pfeilstöcker, M., Stauder, R., et al.[2022]

5-Azacytidine is an effective treatment for patients with myelodysplastic syndromes (MDS), improving overall survival and quality of life, and is the first approved agent for this condition.

The drug works by incorporating into DNA and blocking DNA methyltransferase, leading to hypomethylation and re-expression of silenced genes, and is currently being studied for oral administration and in combination with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-Azacytidine for the treatment of myelodysplastic syndromes. Krawczyk, J., Keane, N., Freeman, CL., et al.[2013]

In a retrospective study of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with hypomethylating agents from 2005 to 2020, decitabine (DAC) showed a significantly higher remission rate in MDS patients compared to azacitidine (AZA) (p = 0.032).

For AML patients, there was no significant difference in outcomes between those treated with AZA and DAC, indicating that both treatments are similarly effective in this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of hypomethylating agents in hematologic malignancies: treatment preferences and results. Serin, I., Dogu, MH.[2022]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

5-aza-2'deoxycytidine (Aza) effectively induces hypomethylation in normal fibroblast cells, but it has unique effects compared to DNMT1 inhibition through siRNA, including specific hypermethylation at various genome sites.

While both Aza and DNMT1 siRNA lead to overall hypomethylation, Aza is less efficient at demethylating gene bodies, suggesting that its off-target effects may limit its broader application in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of DNMT1 inhibitors by methylome profiling identifies unique signature of 5-aza-2'deoxycytidine. Mackin, SJ., O'Neill, KM., Walsh, CP.[2019]

In a study of 243 patients with higher risk myelodysplastic syndrome (MDS) treated with azacitidine, the presence of complex karyotype (CK) was linked to significantly poorer response and overall survival outcomes.

The study found that a higher number of chromosomal abnormalities (CAs) correlated with worse survival, indicating that both CK and the number of CAs are critical prognostic factors in determining treatment outcomes for MDS patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monosomal and complex karyotypes as prognostic parameters in patients with International Prognostic Scoring System higher risk myelodysplastic syndrome treated with azacitidine. Hwang, KL., Song, MK., Shin, HJ., et al.[2020]

In a study comparing azacitidine (AZA-7d) and decitabine (DEC-5d) in 149 patients with myelodysplastic syndrome (MDS), decitabine showed a significantly higher rate of hematologic response (29.7% vs. 12.0%) compared to azacitidine, indicating it may be more effective for some patients.

While both treatments had similar overall survival rates at 2 years (around 42%), azacitidine was associated with better survival in patients with longer MDS duration or poorer performance status, suggesting that treatment choice may depend on individual patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of 7-day azacitidine and 5-day decitabine for treating myelodysplastic syndrome. Lee, JH., Choi, Y., Kim, SD., et al.[2022]

In a study of 315 patients with higher-risk myelodysplastic syndrome (HR-MDS) treated with azacitidine, serum albumin levels were found to be an independent predictor of early treatment failure, indicating that monitoring this level could help identify patients at higher risk for poor outcomes.

The study reported a median survival of 15 months for patients receiving azacitidine, with lower serum albumin levels, serious infections, and receiving fewer than 4 treatment cycles being associated with worse overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low serum albumin level deteriorates prognosis in azacitidine-treated myelodysplastic syndromes patients - results of the PALG study 'PolAZA'. Mądry, K., Lis, K., Tukiendorf, A., et al.[2022]

The combination of decitabine and idarubicin showed a synergistic effect in inducing cell death in various myeloid leukemia cell lines and primary AML cells, suggesting a more effective treatment strategy than decitabine alone.

This combination therapy not only inhibited tumor growth more effectively in mouse models but also triggered apoptosis and downregulated the Wnt/β-catenin pathway, which is linked to leukemia progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. Li, K., Hu, C., Mei, C., et al.[2021]

In a phase 2 study involving 32 elderly patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS), the combination of azacitidine and lenalidomide showed a modest overall response rate of 25%.

Patients who responded to the treatment had a median overall survival of 9.8 months, compared to 4.0 months for non-responders, indicating that the combination may provide significant benefits for those who do respond, despite the treatment being primarily well-tolerated with neutropenic fever as the most common serious side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Narayan, R., Garcia, JS., Percival, ME., et al.[2022]

In a study of 14 patients with myelodysplastic syndrome (MDS) who did not respond to azacitidine, treatment with decitabine resulted in a 28% overall response rate, including three complete remissions.

Decitabine was associated with minimal grade 3-4 drug-related side effects, indicating that it can be a safe and effective treatment option for patients who have failed azacitidine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. Borthakur, G., Ahdab, SE., Ravandi, F., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2817034/

5-azacitidine prolongs overall survival in patients with ... Patients with intermediate-2 and high-risk myelodysplastic syndrome (MDS) have a survival rate of 0.4 to 1.2 years as well as a high risk of their disease ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4603/530151/Azacitidine-Versus-Decitabine-for-the-Treatment-of

Azacitidine Versus Decitabine for the Treatment of ... This study demonstrates that the choice of HMA for the treatment of MDS may have significant impact on patient outcomes, while in the past they ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2817042/

Decitabine versus 5-azacitidine for the treatment of ... As shown in Figure 1C, an indirect comparison of 5-azacitidine versus decitabine showed a statistically significant benefit for the outcome of overall survival ...

4. hematologyadvisor.com hematologyadvisor.com/reports/myelodysplastic-syndrome-mds-azacitidine-improve-outcomes-treatment/

5-Day Azacitidine May Improve Outcomes Compared With ... In the 3-day decitabine, 3-day azacitidine, and 5-day azacitidine groups, the overall response rates were 55%, 57%, and 48%, respectively, ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02269280

Study Details | NCT02269280 | Phase II Decitabine (DAC) ... This is an investigational study. Decitabine and azacitidine are both FDA approved and commercially available for use in patients with MDS. Giving these drugs ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2948932/

Safety and efficacy of azacitidine in myelodysplastic ... Azacitidine is the first drug FDA-approved for the treatment of myelodysplastic syndromes that has demonstrated improvements in overall survival.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6614132/

Real Life Data on Efficacy and Safety of Azacitidine ... The most common toxicity of AZA therapy was myelosuppression and infections. AZA treatment was effective in a limited number of patients with ...

8. ashpublications.org ashpublications.org/blood/article/110/7/2302/103627/Safety-and-clinical-activity-of-the-combination-of

Safety and clinical activity of the combination of 5-azacytidine ... As a single agent, VPA has modest clinical activity in MDS14 and AML.15 In combination with decitabine, VPA has synergistic antileukemic activity in vitro,9 and ...